Carbostyril derivatives

ABSTRACT

Carbostyril derivatives useful for inhibiting the adhesion of platelets represented by general formula ##STR1## [wherein, R 1  is a hydrogen atom, a fluorine atom or a methyl group; R is a group of the formula ##STR2## (R 2  is a methyl group, a trifluoromethyl group or a nitro group), or a group of the formula ##STR3## (R 3  is a fluorine atom and p is an integer of 2 or 3); and n is an integer of 2 or 3], or salts thereof. 
     Said carbostyril derivatives or salts are useful as an agent for inhibiting the adhesion of platelets.

This application is the National phase of PCT/JP94/00760 filed on May11, 1994.

INDUSTRIAL FIELD OF UTILIZATION

The present invention relates to novel carbostyril derivatives.

DISCLOSURE OF THE INVENTION

The carbostyril derivatives of the present invention are represented bythe following general formula (1): ##STR4## [wherein, R¹ is a hydrogenatom, a fluorine atom or a methyl group; R is a group of the formula##STR5## (R² is a methyl group, a trifluoromethyl group or a nitrogroup), or a group of the formula ##STR6## (R³ is a fluorine atom and pis an integer of 2 or 3); and n is an integer of 2 or 3].

The carbostyril derivatives of the present invention have a strongactivity for inhibiting the adhesion of platelets and show low adverseeffects to the cardiovascular system, etc., and are useful agent fortreatment and prevention of arteriosclerotic diseases and thromboticdiseases.

PRIOR ART

Japanese Patent Application Kokai (Laid-Open) No. 45220/1988(corresponding to EP-A-0240015 and U.S. Pat. No. 5,008,274) disclosesthe carbostyril compounds represented by the following general formula:##STR7## (wherein, R is an unsaturated heterocyclic residual grouphaving 1 to 4 hetero atoms selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom; said unsaturatedheterocyclic residual group may have, on the heterocyclic residual ring,1 to 3 substituents selected from the group consisting of an oxo group;a thio group; a phenyl group; a phenyl group which may have, on thephenyl ring, 1 to 3 substituents selected from the group consisting of alower alkyl group, a halo-lower alkyl group, a halogen atom, a hydroxylgroup, an amino group, a lower alkylamino group, a carboxyl group and alower alkoxy group; a cycloalkyl group; a phenylthio group; a loweralkyl group; a lower alkyl group having 1 to 2 substituents selectedfrom the group consisting of an amino group, a lower alkylamino groupand a carboxyl group; an amino group; a hydroxyl group; a cyano group; acarboxyl group; a lower alkoxycarbonyl group; a phenyl-lower alkyl groupwhich may have hydroxyl groups as the substituents on the phenyl ring; aphenylsulfonyl group which may have lower alkyl groups as thesubstituents on the phenyl ring; a lower alkoxy-substituted phenyl-loweralkyl group; a lower alkylthio group; a lower alkenyl group; a loweralkoxy group and a pyridyl group;

R¹ is a hydrogen atom, a lower alkyl group or a phenyl-lower alkylgroup;

R² is a hydrogen atom, a halogen atom, a lower alkylsulfonyloxy group, alower alkoxy group or a hydroxyl group;

Z is an oxygen atom, a sulfur atom, a group of the formula ##STR8## agroup of the formula ##STR9## a group of the formula ##STR10## (whereinR³ is a hydrogen atom or a lower alkyl group) or a group of the formula--NH--;

A is a lower alkylene group;

X is an oxygen atom, a sulfur atom, a group of the formula --SO-- or agroup of the formula --SO₂ --;

n is an integer of 0 or 1; and

the carbon-carbon bond between 3- and 4-positions in the carbostyrilskeleton is a single or double bond).

Since said carbostyril derivatives and salt thereof possess activitiesfor inhibition of thrombotic adhesion, they can be used not only for thetreatment and prevention of arteriosclerosis, ischemic heart disease,chronic arterial obstruction, and acute or chronic nephritis, but alsoin the treatment of artificial dialysis and implantation of artificialorgans, etc.

Some of the carbostyril derivatives of the present invention representedby the above general formula (1) are similar, in chemical structure, tothe above-mentioned carbostyril compounds disclosed in prior artliteratures, but none of the present carbostyril derivatives isdisclosed therein. Further, as shown in the pharmacological test resultsgiven later, the present carbostyril derivatives have a very strongactivity for inhibiting the adhesion of platelets, even when comparedwith the prior art compounds having chemical structures most similar tothose of the present carbostyril derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Ateriosclerosis is an arterial lesion associated with the hypertrophy,sclerosis and regression of arterial wall, is often complicated bythrombosis, and allows the tissues of various organs (e.g., brain, heartand peripheral blood vessels) to have ischemic diseases. As well known,platelets are deeply connected with the onset and progress ofarteriosclerosis (cf., Russell Ross et al., Proc. Natl. Acad. Sci. USA,Vol. 71, p. 1207, 1974; and Russell Ross et al., New Engl. J. Med. Vol.314, p. 488, 1986). That is, in the first stage of arteriosclerosisonset, endothelial cells of artery are peeled by disturbance factorssuch as hypertension, hyperlipidemia, smoking, hormones, bacteria,serotonin, thromboxane A₂ and the like; and platelets adhere onto theinjured arterial walls. This adhesion of platelets is an initialreaction in the formation of thrombus. The adhered platelets causeagglutination with other platelets via fibrinogen and, from the granulesin the agglutinated platelets, there are released, outside the cells,physiologically active substances such as thromoxane A₂, serotonin, ADP(adenosine diphosphate), PDGF (platelet-derived growth factor) and thelike. The released thromboxane A₂, serotonin and ADP injure the tunicaintima of artery and the PDGF gives rise to (1) the migration of smoothmuscle cells of arterial tunica media into arterial tunica intima and(2) the proliferation of smooth muscle cells, which invites thehypertrophy of arterial tunica intima and promotes arteriosclerosis.Hence, substances having an activity for inhibiting the adhesion ofplatelets can inhibit the hypertrophy of arterial tunica intima or theagglunitization of platelets and thereby can be effectively used for thetreatment and prevention of ischemic diseases such as arteriosclerosisand thrombosis.

A number of antiplatelets drugs have been developed as a remedy forischemic diseases. They are for the inhibition of agglutination ofplatelets and inhibit the formation of thrombus in blood stream, but donot inhibit the hypertrophy of arterial tunica intima. The carbostyrilderivatives of the present invention inhibit both the formation ofthrombus and the hypertrophy of arterial tunica intima and therebymaintains normal blood stream. In clinical applications, the presentcarbostyril derivatives can be effectively used for the treatment andprevention of cerebral diseases such as cerebral infarction, transientcerebral ischemic attack, cerebral arteriosclerosis and the like; heartdiseases such as myocardial infarction, cardiac angina and the like;peripheral circulatory diseases such as chronic arteriosclerosis,Bueger's disease and the like; renal diseases such asglomerulonephritis, renal hypertension and the like; and so forth. Thepresent carbostyril derivatives can also be used for blood circulatoryreconstruction operations such as artificial blood vesseltransplantation and the like; prevention of restenosis in percutaneousblood circulation reconstructive operations such as PTA (percutaneoustransluminal angioplasty), PTCA (percutaneous transluminal coronaryangioplasty), PTCR (percutaneous transluminal coronary recanalization)and the like; improvements in blood circulation in artificial dialysis,embedding of artificial organ, intermittent claudication, collagendisease, diabetes mellitus, occupational health hazard due to localvibration, etc.; and improvements in neurotic symptoms and syndromes.

The present compounds represented by general formula (1) include:

1 compounds of general formula (1) wherein R¹ is a hydrogen atom and Ris a group of the formula ##STR11## (R² is the same as defined above), 2compounds of general formula (1) wherein R¹ is a hydrogen atom and R isa group of the formula ##STR12## (R³ and p are the same as definedabove), 3 compounds of general formula (1) wherein R¹ is a fluorine atomand R is a group of the formula ##STR13## (R² is the same as definedabove), 4 compounds of general formula (1) wherein R¹ is a fluorine atomand R is a group of the formula ##STR14## (R³ and p are the same asdefined above), 5 compounds of general formula (1) wherein R¹ is amethyl group and R is a group of the formula ##STR15## (R² is the sameas defined above), and 6 compounds of general formula (1) wherein R¹ isa methyl group and R is a group of the formula ##STR16## (R³ and p arethe same as defined above).

In the above compounds, R¹ is particularly preferably a hydrogen atom;the group of the formula ##STR17## is particularly preferably2-methylphenyl, 2-nitrophenyl or 2-trifluoromethylphenyl; the group ofthe formula ##STR18## is particularly preferably 2,3,4-trifluorophenyl,2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl or 2,4-difluorophenyl; andn is particularly preferably 3.

The present carbostyril derivatives include racemic compounds, S--(+)compounds and R--(-) compounds. Among of them, S--(+) compounds areparticularly preferable.

The carbostyril derivatives of general formula (1) according to thepresent invention can be produced by various processes. Examples of theprocesses include those represented by the following reaction formulas.##STR19## (wherein, R, R¹ and n are the same as defined above; and X isa halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxygroup or an aralkylsulfonyloxy group).

Specific examples of the lower alkanesulfonyloxy group represented by Xare methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy,isopropanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy,pentanesulfonyloxy and hexanesulfonyloxy groups. Specific examples ofthe arylsulfonyloxy group are phenylsulfonyloxy,4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,3-chlorophenylsulfonyloxy and α-naphthylsulfonyloxy groups. Specificexamples of the aralkylsulfonyloxy group are benzylsulfonyloxy,2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy,4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy,4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy,3-chlorobenzylsulfonyloxy and α-naphthylmethylsulfonyloxy groups.Specific examples of the halogen atom are fluorine, chlorine, bromineand iodine atoms.

The reaction of the compound of general formula (2) with the compound ofgeneral formula (3) can be conducted in an appropriate solvent or in theabsence of any solvent, in the presence of a basic compound. The basiccompound can be selected widely from known basic compounds and includesinorganic bases such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, silver carbonate and the like; alkali metals such assodium, potassium and the like; alcholates such as sodium methylate,sodium ethylate, potassium t-butoxide and the like; and organic basessuch as triethylamine, pyridine, N,N-dimethylamine, N-methylmorpholine,4-dimethylaminopyridine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN),1,8-diazabcyclo[5,4,0]undecene-7 (DBU), 1,4-diazabicyclo[2,2,2 octane(DABCO) and the like. As to the solvent, any one of inert solvents whichdoes not give adverse effect to the reaction can be used and includes,for example, alcohols such as methanol, ethanol, propanol, isopropanol,butanol, ethylene glycol and the like; ethers such as dimethyl ether,tetrahydrofuran, dioxane, monoglyme, diglyme and the like; ketones suchas acetone, methyl ethyl ketone and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like; esters such as methyl acetate,ethyl acetate and the like; and aprotic polar solvents such asN,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric triamide (HMPA) and the like. The reaction may beconducted in the presence of a metal iodide such as sodium iodide,potassium iodide or the like. The proportions of the compound (2) andthe compound (3) used in the above reaction have no particularrestriction and can be appropriately selected from a wide range thus,desirably, the latter compound is used in an amount of generally about1-5 moles, preferably about 1-3 moles per mole of the former compound.The reaction temperature may not particularly restricted, and isgenerally about room temperature to 200° C., preferably about 50°-150°C. The reaction is completed generally in about 5 minutes to 30 hours.

The oxidation of the compound (4) is conducted in the presence of anoxidizing agent, in an appropriate solvent. The oxidizing agent can beany known oxidizing agent capable of oxidizing a sulfide group into asulfoxide group, and includes, for example, peracids such as performicacid, peracetic acid, trifluoroperacetic acid, perbenzoic acid,m-chloroperbenzoic acid, o-carbonylperbenzoic acid and the like;hydrogen peroxide; combinations of (1) an alkylhydroperoxide such astert-butyl hydroperoxide, cumene hydroperoxide or the like and (2) atitanium tetraalkoxide such as titanium tetraisopropoxide or the like;bichromic acid; bichromic acid salts such as sodium bichromate,potassium bichromate and the like; permanganic acid; and permanganicacid salts such as sodium permanganate, potassium permanganate and thelike. The solvent includes water; organic acids such as formic acid,acetic acid, trifluoroacetic acid and the like; alcohols such asmethanol, ethanol and the like; halogenated hydrocarbons such aschloroform, dichloroethane, dichloromethane and the like; and mixturesthereof. The reaction proceeds favorably generally at -20° C. to 40° C.,preferably at about -20° C. to room temperature and is completegenerally in about 0.5-70 hours. The desirable amount of the oxidizingagent used is generally at least 1 mole, preferably about 1-1.5 molesper mole of the compound (4). The amount is preferably about 1-5 molesper mole of the compound (4) when the oxidizing agent used is acombination of an alkyl hydroperoxide and a titanium tetraalkoxide.

In the above reaction, by adding, to the reaction system, an agent forasymmetric induction such as optically active dialkyl tartrates [e.g.,D--(-) diethyl tartrate or L--(+) diethyl tartrate] or naphthols (e.g.,binaphthol), there can be obtained an optically active compound (1) at ahigh yield and at a high purity. The optically active compound (1) issubjected to several times of recrystallization by an ordinary method,whereby it can be made into a compound (1) of higher purity. The amountof the agent for asymmetric induction used is desirably about 1-5 molesper mole of the compound (4). The oxidizing agent used when an opticallyactive compound (1) is obtained, is particularly preferably acombination of an alkyl hydroperoxide and a titanium tetraalkoxide. Whenthis oxidizing agent is used, the reaction proceeds favorably by theaddition of a molecular sieve or water in an amount of 0.1-1 equivalentrelative to the compound (4). ##STR20## (wherein, R¹, R², n and X arethe same as defined above; and R⁴ is a chlorine atom, a bromine atom oran iodine atom).

The reaction of the compound (2) with the compound (5) and the oxidationof the compound (6) can be conducted under the same conditions as in thereaction of the compound (2) with the compound (3) and the oxidation ofthe compound (4) in the Reaction formula-1, respectively.

The reaction for converting the compound (7) into a compound (1a) can beconducted by catalytic reduction. As to the catalyst for catalyticreduction, there can be used those of ordinary use, such as platinumoxide, platinum, platinum black, palladium, palladium black,palladium-carbon, Raney nickel and the like. The desirable amount of thecatalyst used is generally about 0.02-1 time the weight of the compound(7) used. The catalytic reduction is conducted in a solvent such aswater, lower alcohol (e.g., methanol, ethanol or isopropanol), ether(e.g., tetrahydrofuran or diethyl ether) or the like in a hydrogenatmosphere of generally 1-20 atm., preferably 1-10 atom. with sufficientshaking. The reduction is conducted generally at -30° C. to the boilingpoint of the solvent used, preferably at about 0°-100° C. and iscomplete generally in about 0.5-20 hours. The reaction proceedsfavorably by the addition of a basic compound (e.g., triethylamine) tothe reaction system.

The compound (7) is useful as an intermediate for synthesis of compound(1). When there is used, for example, an optically active compound (7)as said intermediate, an optically active compound (1) can be obtainedat a high yield at a high purity. ##STR21## (wherein, R, R¹, n and X arethe same as defined above; and R⁵ is a hydrogen atom or an alkali metalsuch as sodium, potassium or the like).

The reaction of the compound (8) with the compound (9) and the reactionof the compound (8) with the compound (10) are conducted under the sameconditions as employed in the reaction of the compound (2) with thecompound (3) in the Reaction formula-1, except that the compound (8) isused in an amount of generally about 1-5 moles, preferably about 1-2moles per mole of the compound (9) or the compound (10). The oxidationof the compound (4) was described in the Reaction formula-1. ##STR22##(wherein, R¹ and n are the same as defined above; X¹ is a halogen atomor an arylsulfonyloxy group; and R⁶ and R⁷ independently represent alower alkyl group).

The reaction of the compound (11) with the compound (12) can beconducted in the presence of a solvent. The solvent includes, forexample, aromatic hydrocarbons such as benzene, toluene, xylene and thelike; lower alcohols such as methanol, ethanol, isopropanol and thelike; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethylether, diethyl ether and the like; and polar solvents such asN-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide,hexamethylphosphoric triamide and the like. The reaction may use a basiccompound as an acid remover to allow the reaction to proceed morefavorably. The basic compound can be exemplified by potassium carbonate,sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodiumamide, sodium hydride, tertiary amines (e.g. triethylamine andtripropylamine), pyridine and quinoline. The desirable amount of thecompound (11) used is generally at least 1 mole, preferably 1-2 molesper mole of the compound (12). The reaction is desirably conductedgenerally at room temperature to 150° C., preferably at room temperatureto 100° C. and is complete generally in about 1.5-15 hours.

Successively, hydrolysis is conducted by a treatment in the presence ofa mineral acid such as hydrochloric acid, sulfuric acid or the like, ina solvent such as water, alcohol (e.g., methanol, ethanol orisopropanol), ether (e.g., diethyl ether or tetrahydrofuran) or thelike, at room temperature to the boiling point of the solvent used, for30 minutes to 15 hours.

The reaction of the compound (13) with malonic acid (14) is conducted inan appropriate solvent in the presence of a basic compound. The solventmay be any solvent used in the reaction of the compound (1) with thecompound (12), or a polar solvent such as pyridine or the like. Thebasic compound can be exemplified by inorganic bases such as potassiumcarbonate, sodium carbonate, sodium hydroxide, sodium hydrogencarbonate,sodium amide, sodium hydride and the like, and organic bases such astriethylamine, tripropylamine, piperidine, pyridine, quinoline and thelike. The proportions of the compound (13) and malonic acid (14) usedare desirably such that the amount of the latter is at least 1 mole,generally 2-7 moles per mole of the former. The reaction is conductedgenerally at 0°-200° C., preferably at about 70°-150° C. and is completein about 1-10 hours.

The reaction for converting the compound (15) into a compound (1) isconducted, for example, by reducing the compound (15) with a catalystfor catalytic reduction, in an appropriate solvent. The solventincludes, for example, water; acetic acid; alcohols such as methanol,ethanol, isopropanol and the like; hydrocarbons such as hexane,cyclohexane and the like; ethers such as diethylene glycol dimethylether, dioxane, tetrahydrofuran, diethyl ether and the like; esters suchas ethyl acetate, methyl acetate and the like; and aprotic polarsolvents such as N,N-dimethylformamide and the like. As to the catalystfor catalytic reduction, there are used, for example, palladium,palladium black, palladium-carbon, platinum, platinum oxide, copperchromite and Raney nickel. The amount of the catalyst used is desirably0.02-1 time the weight of the compound (15). The reaction is conductedat a hydrogen pressure of 1-10 atm. generally at about room temperatureto 200° C., preferably at about 50°-150° C., and is complete in about0.5-10 hours. The reaction proceeds favorably by the addition of a basiccompound (e.g., triethylamine) to the reaction system.

In the reaction formula-3 and the Reaction Formula-4, when an opticallyactive compound is used as the compound (10) or (12), an opticallyactive compound (1) can be obtained.

In each of the above reaction formulas, the compounds (3), (5), (9),(10) and (12) each used as a starting material can be produced, forexample, by the processes represented by the following reactionformulas. ##STR23## (wherein, R, R², R⁴, R⁶ and R⁷ are the same asdefined above).

The reaction for converting the compound (16) into a compound (17) andthe reaction for converting the compound (18) into a compound (19) canbe conducted by (1) reacting the compound (16) or (18) with thiophosgenein an appropriate solvent or (2) reacting the compound (16) or (18) withcarbon disulfide in an appropriate solvent in the presence of a basiccompound, and successively reacting the reaction product with adehydrating agent such as dicyclohexylcarbodiimide, carbonylimidazole orthe like in an appropriate solvent.

The solvent used in the above reaction (1) may be any solvent which doesnot adversely affect the reaction, and can be exemplified by alcoholssuch as ethanol, methanol, isopropanol and the like; halogenatedhydrocarbons such as chloroform, dichloromethane, carbon tetrachlorideand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; ethers such as dioxane, diethylene glycol dimethyl ether,diethyl ether, tetrahydrofuran and the like; and polar solvents such asdimethyl sulfoxide, hexamethylphosphoric triamide and the like. Thereaction (1) is conducted generally at room temperature to 150° C.,preferably at about room temperature to 100° C. and is complete in about1-10 hours. The desirable amount of the compound (16) or (18) used is atleast 1 mole, preferably 1-3 moles per mole of thiophosgene.

The solvent used in the above reaction (2) may be any solvent used inthe reaction (1) or other solvent such as pyridine or the like. Thebasic compound can be exemplified by inorganic bases such as sodiumhydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, potassium carbonate,sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium,metallic potassium, sodium amide and the like, and organic bases such asN,N-dimethylaniline, piperidine, pyridine, triethylamine, sodiumacetate, potassium acetate and the like. The reaction (2) is conductedgenerally at 0°-100° C., preferably at 0°-70° C. and is completegenerally in about 1-15 hours. The desirable amount of carbon disulfideused is generally 1-20 moles, preferably 1-10 moles per mole of thecompound (16) or (18).

In the subsequent reaction with a dehydrating agent, the solvent usedmay be any solvent used in the above reaction of the compound (16) or(18) with carbon disulfide. The reaction is conducted generally at0°-100° C., preferably at 0°-70° C. and is complete generally in about1-15 hours. The desirable amount of the dehydrating agent used is atleast 1 mole, preferably 1-2 moles per mole of the compound (16) or(18).

The reaction of the compound (17) with the compound (20) and thereaction of the compound (19) with the compound (20) are conducted inthe presence of an appropriate solvent or in the absence of any solvent.The solvent may be any solvent mentioned in the reaction (1) forconverting the compound (16) or (18) into a compound (17) or (19). Thereaction is conducted generally at 0°-200° C., preferably at about0°-150° C. and is complete generally in about 5 minutes to 5 hours. Thedesirable amount of the compound (20) used is at least 1 mole,preferably 1-2 moles per mole of the compound (17) or (19).

The subsequent reaction for alcohol removal is conducted in anappropriate solvent or in the absence of any solvent, in the presence ofa mineral acid such as hydrochloric acid, sulfuric acid or the like atroom temperature to 150° C., preferably at about room temperature to120° C., and is complete in about 10 minutes to 10 hours. The solventused can be exemplified by water; alcohols such as methanol, ethanol,isopropanol and the like; ethers such as diethyl ether, tetrahydrofuranand the like; and mixtures thereof. ##STR24## (wherein, R, n, X¹ and Xare the same as defined above).

The reaction of the compound (3) with the compound (21) is conductedunder the same conditions as in the Reaction of the compound (2) withthe compound (3) in the Reaction formula-1. The oxidation of thecompound (22) is conducted under the same conditions as in the oxidationof the compound (4) in the Reaction formula-1.

The reaction for converting the compound (22) into a compound (9) andthe reaction for converting the compound (12) into a compound (10) areconducted as follows. For example, when X is a halogen atom in thecompound (9) or (10), said reactions are each conducted in the presenceof a halogenating agent in an appropriate solvent or in the absence ofany solvent. The halogenating agent can be exemplified by hydrohalogenicacids such as hydrochloric acid, hydrobromic acid and the like;N,N-diethyl-1,2,2-trichlorovinylamide; phosphorus pentabromide;phosphorus oxychloride; and thionyl chloride. The desirable amount ofthe halogenating agent used is at least equimolar, generally a largeexcess over the compound (22) or (12). The solvent can be exemplified byethers such as dioxane, tetrahydrofuran, diethyl ether and the like, andhalogenated hydrocarbons such as chloroform, methylene chloride, carbontetrachloride and the like. The above reactions each proceed generallyat -20° C. to 150° C., preferably at -20° C. to 80° C., and are completegenerally in about 10 minutes to 6 hours.

When X is a lower alkanesulfonyloxy group, an arylsulfonyloxy group oran aralkylsulfonyloxy group in the compound (9) or (10), each reactionis conducted by reacting the compound (22) or (12) with a compoundrepresented by general formula R⁸ X¹ (23) (R⁸ is a lower alkanesulfonylgroup, an arylsulfonyl group or an aralkylsulfonyl group, and X¹ is thesame as defined above) in an appropriate solvent in the presence of abasic compound. The solvent and the basic compound can each be any onedescribed in the reaction of the compound (2) with the compound (3) inthe Reaction formula-1. Each reaction is conducted generally at 0°-200°C., preferably at about 0°-100° C., and is complete generally in about 5minutes to 10 hours. The desirable amount of the compound (23) used isat least 1 mole, preferably 1-2 moles per mole of the compound (22) or(12).

Each of the intended compounds obtained by the above reaction formulascan be easily separated from the reaction system and purified byordinary means. The means for separation can be exemplified by solventextraction, dilution, recrystallization, column chromatography andpreparative thin-layer chromatography.

Needless to say, the compounds of the present invention include opticalisomers and stereoisomers.

Each of the compounds of the present invention is used generally in theform of ordinary pharmaceutical preparation. The pharmaceuticalpreparation is prepared by using diluents or excipients ordinarily used,such as filler, bulking agent, binder, humectant, disintegrator,surfactant, lubricant and the like. The pharmaceutical preparation canbe prepared in various forms depending upon the purpose of remedy, andthe typical forms include tablets, pills, a powder, a solution, asuspension, an emulsion, granules, capsules, suppositories, an injection(e.g. solution or suspension), etc. In preparing tablets, there can beused various carriers known in the art. The carriers can be exemplifiedby excipients such as lactose, white sugar, sodium chloride, glucose,urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicicacid and the like; binders such as water, ethanol, propanol, simplesyrup, glucose solution, starch solution, gelatin solution,carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate,polyvinylpyrrolidone and the like; disintegrators such as dry starch,sodium alginate, powdered agar, powdered laminarin, sodiumhydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan-fattyacid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch,lactose and the like; disintegration inhibitors such as white sugar,stearin, cacao butter, hydrogenated oil and the like; absorptionpromoters such as quaternary ammonium salts, sodium lauryl sulfate andthe like; humectants such as glycerine, starch and the like; adsorbentssuch as starch, lactose, kaolin, bentonite, colloidal silicic acid andthe like; and lubricants such as refined talc, stearic acid salts, boricacid powder, polyethylene glycol and the like. The tablets can beprepared, as necessary, in the form of ordinary coated tablets, such assugar-coated tablets, gelatin-coated tablets, enteric coated tablets orfilm-coated tablets, or in the form of double-layered tablets ormulti-layered tablets. In preparing pills, there can be used variouscarriers known in the art. The carriers can be exemplified by excipientssuch as glucose, lactose, starch, cacao butter, hardened vegetable oils,kaolin, talc and the like; binders such as powdered acacia, powderedtragacanth, gelatin, ethanol and the like; and disintegrators such aslaminarin, agar and the like. In preparing suppositories, there can beused carriers known in the art. The carriers can be exemplified by apolyethylene glycol, cacao butter, a higher alcohol, a higher alcoholester, gelatin and a semi-synthetic glyceride. In preparing an injection(solution, emulsion or suspension), it is sterilized and is preferablymade isotonic to the blood. In preparing the solution, emulsion orsuspension, there can be used all diluents ordinarily used in the art,such as water, aqueous lactic acid solution, ethyl alcohol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxy-isostearyl alcohol andpolyoxyethylene sorbitan-fatty acid esters. In this case, the injectionmay contain sodium chloride, glucose or glycerine in an amountsufficient to make the injection isotonic, and may further contain asolubilizing agent, a buffer solution, a soothing agent, etc. allordinarily used. The pharmaceutical preparation may furthermore contain,as necessary, a coloring agent, a preservative, a perfume, a flavoringagent, a sweetening agent and other drugs. In preparing the presentpharmaceutical preparation in the form of a paste, a cream or a gel,there can be used diluents such as white petrolatum, paraffin, glycerin,cellulose derivatives, polyethylene glycol, silicon, bentonite and thelike.

The amount of the compound of general formula (1) or the salt thereof tobe contained in the pharmaceutical preparation of the present inventionis not particularly restricted and can be appropriately selected from awide range, but the desirable amount is generally 1-70% by weight in thepharmaceutical preparation.

The method for administering the pharmaceutical preparation of thepresent invention is not particularly restricted. It is decideddepending upon the form of preparation, the age, distinction of sex andother conditions of patient, the disease condition of patient, etc. Forexample, tablets, pills, a solution, a suspension, an emulsion, granulesor capsules are administered orally. An injection is intravenouslyadministered singly or in admixture with an ordinary auxiliary solutionof glucose, amino acids or the like, or, as necessary, is singlyadministered intramuscularly, intradermally, subcutaneously orintraperitoneally. Suppositories are administered intrarectally.

The dose of the pharmaceutical preparation of the present invention isappropriately selected depending upon the administration method, theage, distinction of sex and other conditions of patient, the diseasecondition of patient, etc., but the desirable dose is generally about0.06-100 mg per kg of body weight per day in terms of the amount of theactive ingredient, i.e. the compound of general formula (1) or the saltthereof. The pharmaceutical preparation can be administered in 2 to 4portions in a day.

The present invention is hereinafter described specifically by way ofPreparation Examples, Reference Examples, Examples and PharmacologicalTest.

PREPARATION EXAMPLE 1 Preparation of tablets

    ______________________________________                                        Component                Amount (g)                                           ______________________________________                                        6-{3-[1-(2-Nitrophenyl)-2-imidazolyl]-                                                                 5                                                    sulfinylpropoxyl}-3,4-dihydrocarbostyril                                      Lactose (Japanese Pharmacopoea grade)                                                                  50                                                   Corn starch (Japanese Pharmacopoea grade)                                                              25                                                   Crystalline cellulose (Japanese                                                                        25                                                   Pharmacopoea grade)                                                           Methyl cellulose (Japanese Pharmacopoea                                                                1.5                                                  grade)                                                                        Magnesium stearate (Japanese                                                                           1                                                    Pharmacopoea grade)                                                           ______________________________________                                    

The above compound of the present invention, lactose, corn starch andcrystalline cellulose were mixed thoroughly. The mixture was made intogranules using a 5% aqueous methyl cellulose solution. The granules werepassed through a 200-mesh sieve and then dried carefully. The driedgranules were made into 1,000 tablets by an ordinary method.

PREPARATION EXAMPLE 2 Preparation of capsules

    ______________________________________                                        Component               Amount (g)                                            ______________________________________                                        6-{3-[1-(2,4-Difluorophenyl)-2-imidazolyl)-                                                           10                                                    sulfinylpropoxy]-3,4-dihydrocarbostyril                                       Lactose (Japanese Pharmacopoea grade)                                                                 80                                                    Starch (Japanese Pharmacopoea grade)                                                                  30                                                    Talc (Japanese Pharmacopoea grade)                                                                     5                                                    Magnesium stearate (Japanese                                                                           1                                                    Pharmacopoea grade)                                                           ______________________________________                                    

The above components were finely ground and thoroughly mixed to obtain auniform mixture. The mixture was filled into gelatin capsules for oraladministration, each having a desired dimension, whereby 1,000 capsuleswere prepared.

PREPARATION EXAMPLE 3 Preparation of injection

    ______________________________________                                        Component               Amount (g)                                            ______________________________________                                        6-{3-[1-(2-Trifluoromethylphenyl)-2-                                                                  1                                                     imidazolyl]sulfinylpropoxy}-3,4-                                              dihydrocarbostyril                                                            Polyethylene glycol (molecular weight: 4,000)                                                         0.3                                                   (Japanese Pharmacopoea grade)                                                 Sodium chloride         0.9                                                   (Japanese Pharmacopoea grade)                                                 Polyoxyethylene sorbitan monooleate                                                                   0.4                                                   (Japanese Pharmacopoea grade)                                                 Sodium metabisulfite    0.1                                                   Methyl parahydroxybenzoate                                                                            0.18                                                  (Japanese Pharmacopoea grade)                                                 Propyl parahydroxybenzoate                                                                            0.02                                                  (Japanese Pharmacopoea grade)                                                 Distilled water for injection                                                                         100 (ml)                                              ______________________________________                                    

The above parahydroxybenzoates, sodium metabisulfite and sodium chloridewere dissolved in distilled water of about half of the above volume at80° C., with stirring. The solution was cooled to 40° C., and thereinwere dissolved the compound of the present invention, polyethyleneglycol and polyoxyethylene sorbitan monooleate. To the resultingsolution was added the remaining volume of distilled water for finalvolume adjustment, followed by filtration through an appropriate filterpaper for sterilization, whereby an injection was prepared.

Reference Example 1

To 200 ml of benzene were added 22 g of 2-nitroaniline and 6.6 ml ofthiophosgene. The mixture was refluxed for 2 hours. After cooling, theresulting crystals were removed by filtration and the filtrate wasconcentrated. The resulting residue was purified by a silica gel columnchromatography (eluant: ethyl acetate/n-hexane=0/1→1/10) to obtain 8.0 gof 2-nitrophenyl isothiocyanate.

¹ H-NMR (CDCl₃) δ ppm:

7.35-7.50 (2H, m), 7.63 (1H, m),

8.09 (1H, d, J=8 Hz)

Reference Example 2

In 800 ml of pyridine were dissolved 275 ml of carbon disulfide and 93ml of triethylamine. To the solution was added 125 g of4-bromo-2-methylaniline. The mixture was stirred at room temperatureovernight. Thereto was added 138.5 g of 1,3-dicyclohexylcarbodiimide(DCC). The mixture was stirred overnight. Pyridine was removed bydistillation. To the residue was added n-hexane. The resultingprecipitate (DC-thiourea) was removed by filtration. The filtrate wasconcentrated and the residue was purified by a silica gel columnchromatography (eluant: n-hexane) to obtain 138 g of4-bromo-2-methylphenyl isothiocyanate.

White acicular crystals.

Melting point: 43°-45° C.

Reference Example 3

147 Grams of 2,4-difluorophenyl isothiocyanate was obtained by using 100ml of 2,4-difluoroaniline, 138 ml of triethylamine, 400 ml of carbondisulfide, 500 ml of pyridine and 206 g of DCC and by using the sameprocedure as in Reference Example 2.

Colorless oil.

¹ H-NMR (CDCl₃) δ ppm:

6.8-7.0 (2H, m), 7.17 (1H, m)

Reference Example 4

105.5 Milliliters of 2,2-diethoxyethylamine was dropwise added to 138 gof 4-bromo-2-methylphenyl isothiocyanate with ice-cooling. The mixturewas stirred for 10 minutes and then further stirred for 10 minutes at100° C. The mixture was allowed to cool, and thereto was added 500 ml of8 N hydrochloric acid. The mixture was refluxed for 2 hours. Theresulting crystals were collected by filtration, washed with waterthoroughly and then dried to obtain 110 g of1-(4-bromo-2-methylphenyl)-2-mercaptoimidazole.

White prismatic crystals.

Melting point: 241° C. (decomposed)

Reference Example 5

118 Grams of 1-(2,4-difluorophenyl)-2-mercaptoimidazole was obtained byusing 147 g of 2,4-difluorophenyl isothiocyanate, 150 ml of2,2-diethoxyethylamine and 150 ml of 6 N hydrochloric acid and by usingthe same procedure as in Reference Example 4.

White powder.

¹ H-NMR (CDCl₃) δ ppm:

6.91 (1H, s), 6.94 (1H, s), 7.0-7.2 (2H, m), 7.7 (1H, m)

Reference Example 6

2.5 Grams of 1-(2-nitrophenyl)-2-mercaptoimidazole was obtained by using6 g of 2-nitrophenyl isothiocyanate, 5.8 ml of 2,2-diethoxyethylamineand 100 ml of 6 N hydrochloric acid and by using the same procedure asin Reference Example 4.

¹ H-NMR (DMSO-d₆) δ ppm:

7.12 (1H, s), 7.32 (1H, s), 7.61 (1H, d, J=7 Hz), 7.74 (1H, dd, J=7.8Hz), 7.90 (1H, dd, J=7.8 Hz), 8.16 (1H, d, J=8 Hz)

Reference Example 7

In 300 ml of dimethylformamide were dissolved 89 g of6-(3-chloropropoxy)-3,4-dihydrocarbostyril and 110 g of1-(4-bromo-2-methylphenyl)-2-mercaptoimidazole. To the solution wasslowly added 66.7 g of potassium carbonate at room temperature. Themixture was stirred at 80° C. for 2 hours to give rise to a reaction.After the completion of the reaction, the reaction mixture was extractedwith ethyl acetate. The oily layer was washed with water thoroughly,washed with an aqueous solution saturated with sodium chloride, driedwith anhydrous magnesium sulfate, and subjected to distillation toremove the solvent. The resulting brown oil was purified by a silica gelcolumn chromatography (eluant: chloroform/methanol=50/1). The resultingcrude crystals were recrystallized from ethanol to obtain 118 g of6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril.

Colorless prismatic crystals.

Melting point: 117°-120° C.

Reference Example 8

42.4 Grams of6-{3-(2,4-difluorophenyl)-2-imidazolylthio]propoxy-3,4-dihydrocarbostyrilwas obtained by using 40 g of6-(3-chloropropoxy)-3,4-dihydrocarbostyril, 42.6 g of1-(2,4-difluorophenyl)-2-mercaptoimidazole, 36 ml of DBU and 600 ml ofisopropanol and by using the same procedure as in Reference Example 7.

White prismatic crystals (recrystallized from ethanol-n-hexane).

Melting point: 133°-134° C.

Reference Example 9

To 800 ml of dichloroethane sufficiently dried with a molecular sievewere added 52.5 ml of titanium tetraisopropoxide and 119.2 ml ofD-(-)-diethyl tartarate. The mixture was stirred for 30 minutes. In thesolution was dissolved 82 g of6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril.Thereto was added 0.78 ml of water. The mixture was stirred for 30minutes. The reactor inside was sufficiently purged with nitrogen, andthe reactor contents were cooled with methanol-ice. Thereto was added103.8 ml of cumene hydroperoxide. The mixture was stirred to 5° C. for64 hours to give rise to a reaction. After the completion of thereaction, the reaction mixture was purified by a silica gel columnchromatography (eluant: dichlorometane/ethyl acetate/methanol=30/10/1),followed by three times of recrystallization from ethanol, to obtain24.5 g of(S)-(+)-6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.

Colorless prismatic crystals.

Optical purity: nearly 100% (enantiomer excess)

[α]_(D) ²⁴ : 19.6° (c=1.0, methanol)

Melting point: 156°-158° C.

The high performance liquid chromatography used for measurement ofoptical purity was conducted under the following conditions.

Column: DAICEL CHIRALCEL OJ 4.6 mm×250 mm (a product of DAICEL CHEMICALINDUSTRIES, LTD.)

Mobile phase: n-hexane/isopropanol/diethylamine=400/600/1

Flow rate: 0.6 ml/min

Ultraviolet light: 254 nm

Retention time: 34.5 minutes

Reference Example 10

380 Grams of 1-(2-methylphenyl)-2-mercaptoimidazole, 300 g of potassiumcarbonate and 400 g of 3-chlolopropanol were mixed with 5 l ofdimethylformamide. The mixture was stirred at 60° C. for 5 hours. Thereaction mixture was filtered and the filtrate was subjected todistillation under reduced pressure. The residue was dissolved in ethylacetate. The solution was washed with an aqueous solution saturated withsodium chloride, dried with anhydrous magnesium sulfate, and subjectedto distillation to remove the solvent. The residue was dissolved in 1 lof a 1:2 mixture of diethyl ether and n-hexane. The solution was allowedto stand in an ice bath to obtain 430 g of3-[1-(2-methylphenyl)-2-imidazolylthio]propanol.

Colorless acicular crystals.

Melting point: 47°-48° C. (recrystallized from diethyl ether-n-pentane)

¹ H-NMR (CDCl₃) δ ppm: 1.7-1.95 (2H, m), 2.09 (3H, s), 3.32 (2H, t, J=7Hz), 3.74 (2H, t, J=7 Hz), 5.83 (1H, brs), 6.96 (1H, d, J=2 Hz), 7.12(1H, d, J=2 Hz), 7.21 (1H, d, J=7 Hz), 7.27-7.45 (3H, m)

Reference Example 11

To 3 l of dichloroethane were added 123 g of3-[1-(2-methylphenyl)-2-imidazolylthio]propanol, 414 g of L-(+)-diethyltartarate and 120 g of a powder of Molecular Sieve 4A. The mixture wasstirred at room temperature for 2 days. Thereto was added 142 g oftitanium tetraisopropoxide. The mixture was stirred at room temperaturefor 30 minutes. Thereto was added 91 g of cumene hydroperoxide. Themixture was stirred at 5° C. for 24 hours. The reaction mixture per sewas purified by a silica gel column chromatography (eluant:dichloromethane/methanol=50/1). Recrystallization from methyl ethylketone was repeated to obtain 50 g of(S)-(+)-3-[1-(2-methylphenyl)2-imidazolylsulfinyl]propanol.

Colorless acicular crystals.

Optical purity: 100% (enantiomer excess) p1 [α]_(D) ²⁴ : 67.5° (C=1.0,methanol)

Melting point: 111°-111.5° C.

¹ H-NMR (CDCl₃) δ ppm: 1.95-2.25 (5H, m), 2.88 (1H, m), 3.40-3.80 (4H,m), 7.15 (1H, d, J=2 Hz), 7.28-7.55 (5H, m)

The high performance liquid chromatography used for measurement ofoptical purity was conducted under the following conditions.

Column: DAICEL CHIRALCEL OJ 4.6 mm×250 mm (a product of DAICEL CHEMICALINDUSTRIES, LTD.)

Mobile phase: n-hexane/ethanol/diethylamine=800/200/1

Flow rate: 1.0 ml/min

Ultraviolet light: 254 nm

Retention time: 18.5 minutes

Reference Example 12

To 50 ml of dimethylformamide were added 2.9 g of3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propanol and 3.4 g of5-chloro-2-nitro-benzaldehyde dimethylacetal. To the mixture beingstirred was added 0.75 g of 60% sodium hydride slowly. The mixture wasstirred at 60° C. overnight. Thereto was added an aqueous solutionsaturated with ammonium chloride. The reaction mixture was concentrated.The residue was extracted with ethyl acetate. The extract was washedwith water and an aqueous solution saturated with sodium chloride, driedwith magnesium sulfate, and subjected to distillation to remove ethylacetate. The residue was purified by a silica gel column chromatography(eluant: dichloromethane/methanol=1/0→50/1) to obtain 3.3 g of1-(2-methylphenyl)-2-[3-(3-dimethoxymethyl-4-nitrophenoxy)propylsulfinyl]imidazoleas a light yellow oil.

¹ H-NMR (CDCl₃) δ ppm: 2.11 (3H, brs), 2.2-2.4 (2H, m), 3.43 (6H, s),3.50 (1H, m), 3.70 (1H, m), 4.1-4.3 (2H, m), 6.00 (1H, s), 6.85 (1H, dd,J=3 Hz, 9 Hz), 7.18 (1H, s), 7.2-7.5 (5H, m), 7.25 (1H, d, J=3 Hz), 7.95(1H, d, J=9 Hz)

Reference Example 13

3.3 Grams of1-(2-methylphenyl)-2-[3-(3-dimethoxymethyl-4-nitrophenoxy)propylsulfinyl]imidazolewas added to 100 ml of tetrahydrofuran and 10 ml of 4 N hydrochloricacid. The mixture was stirred overnight and extracted with ethylacetate. The extract was washed with water and an aqueous solutionsaturated with sodium chloride, dried with magnesium sulfate, andconcentrated to obtain 2.8 g of1-(2-methylphenyl)-2-[3-(3-formyl-4-nitrophenoxy)propylsulfinyl]imidazoleas a light yellow oil.

¹ H-NMR (CDCl₃) δ ppm: 2.11 (3H, brs), 2.2-2.45 (2H, m), 3.47 (1H, m),3.75 (1H, m), 4.2-4.35 (2H, m), 7.10 (1H, dd, J=3 Hz, 9 Hz), 7.15-7.5(7H, m), 8.15 (1H, d, J=9 Hz), 10.47 (1H, s)

Reference Example 14

To 100 ml of pyridine were added 5.0 g of1-(2-methylphenyl)-2-[3-(3-formyl-4-nitrophenoxy)propylsulfinyl]imidazole,2.0 g of malonic acid and 2 ml of piperidine. The mixture was refluxedfor 2.5 hours. The reaction mixture was subjected to distillation toremove pyridine. The residue was made alkaline with an aqueous potassiumcarbonate solution. The resulting solution was washed with ethyl acetateand extracted with dichloromethane. The methylene chloride layer wasdried with magnesium sulfate and then concentrated. The residue wasrecrystallized from ethanol to obtain 1.7 g of2-nitro-5-{3-[1-(2-methylphenyl)-2-imidazolyl)sulfinyl]propoxy}cinammicacid.

¹ H-NMR (CDCl₃) δ ppm: 1.9-2.2 (5H, m), 3.4 (1H, m), 3.55 (1H, m),4.2-4.6 (2H, m), 6.53 (1H, s, J=16 Hz), 7.14 (1H, d, J=9 Hz), 7.29 (1H,s), 7.3-7.55 (5H, m), 7.67 (1H, s), 7.96 (1H, d, J=16 Hz), 8.11 (1H, d,J=9 Hz ), 12.71 (1H, brs )

Example 1

In a pressure glass reactor containing ethanol was placed 12 g of6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.To the resulting solution were added 18 ml of triethylamine and 6 g of a10% palladium carbon powder. The reactor inside was purged with hydrogengas and the reactor contents were subjected to a reaction at a pressureof 3 kg/cm² at 70° C. for 16 hours. The reaction was repeated on thesame scale. The reaction mixture obtained from two times of the reactionwas filtered to remove the catalyst. The filtrate was extracted withchloroform, washed with 1 N aqueous hydrochloric acid solutionthoroughly, washed with an aqueous solution saturated with sodiumchloride, dried with anhydrous magnesium sulfate, and subjected todistillation to remove the solvent. The resulting white oil was purifiedby a silica gel column chromatography (eluant: dichloromethane/ethylacetate/methanol=30/10/1) to obtain crude crystals. The crude crystalswere recrystallized from ethanol to obtain 13.2 g of(S)-(+)-6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.

White powdery crystals.

Optical purity: 99.4% (enantiomer excess)

[α]_(D) ²⁴ : 17.2° (c=1.0, methanol)

Melting point: 124.5°-126.5° C.

The high performance liquid chromatography used for measurement ofoptical purity was conducted under the following conditions.

Column: ULTRON ES-OVM 4.6 mm×150 mm (a product of Shinwa ChemicalIndustries, Ltd.)

Mobile phase: acetonitrile/20 mM KH₂ PO₄ aq.=8/92

Flow rate: 0.8 ml/min

Ultraviolet light: 254 nm

Retention time: 16.5 minutes

The same conditions were used also in Example 2 and Example 5 whichfollow.

Example 2

3.97 Grams of(S)-(+)-3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propanol and 2.72 mlof triethylamine were mixed with 80 ml of ethyl acetate. Thereto wasadded 1.51 ml of methanesulfonyl chloride at room temperature, and themixture was stirred for 10 minutes. The reaction mixture was washed withan aqueous sodium hydrogencarbonate solution and a saturated aqueoussodium chloride solution in this order, dried with magnesium sulfate,and subjected to distillation to remove the solvent. The residue wasdissolved in 20 ml of dimethyl sulfoxide. This solution is referred toas "solution A".

8.35 Grams of sodium salt of 6-hydroxy-3,4-dihydrocarbostyril was mixedwith 80 ml of dimethyl sulfoxide. Thereto was added solution A at 60°C., and the mixture was stirred for 0.5 hour under the same state. Thereaction mixture was dissolved in ethyl acetate. The solution was washedwith an aqueous solution saturated with sodium chloride, dried withanhydrous magnesium sulfate, and subjected to distillation to remove thesolvent. The residue was purified by a silica gel column chromatography(eluant: dichloromethane/methanol=40/1). The crude crystals wererecrystallized from ethanol to obtain 4.5 g of(S)-(+)-6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.

White powder.

Optical purity: 99.7% (enantiomer excess)

[α]_(D) ²⁴ : 17.2° (c=1.0, methanol)

Melting point: 124.5°-126.5° C.

Example 3

To 50 ml of ethanol were added 300 mg of2-nitro-5-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]-propoxy}cinnamicacid, 100 mg of 10% palladium carbon and 0.6 ml of triethylamine.Hydrogenation was conducted at a hydrogen pressure of 4 atm. at 60° C.for 3 hours. The reaction mixture was cooled to room temperature andfiltered to remove the catalyst. To the filtrate was added 200 mg of 10%palladium carbon, and hydrogenation was conducted at a hydrogen pressureof 4 atm. at 60° C. for 6 hours. Ethanol was removed by distillation.The residue was made acidic with hydrochloric acid, followed byextraction with methylene chloride. The extract was washed with anaqueous solution saturated with sodium chloride, dried with anhydrousmagnesium sulfate, and subjected to distillation to remove the solvent.The residue was purified by a silica gel column chromatography (eluant:dichloromethane/methanol=50/1→20/1). The crude crystals wererecrystallized from ethanol-n-hexane to obtain 70 mg of6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.

White powder.

Melting point: 141.5°-142.5° C.

Example 4

In 1 liter of dichloromethane was dissolved 67 g of6-{3-[1-(2-methylphenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril.Thereto was added 32.6 g of m-chloroperbenzoic acid with ice-cooling.The mixture was stirred overnight. After the completion of the reaction,the reaction mixture was washed five times with an aqueous solutionsaturated with sodium hydrogencarbonate, dried with magnesium sulfate,and subjected to distillation to remove the solvent. The residue waspurified by a silica gel column chromatography (eluant:dichloromethane/ethyl acetate/methanol=30/10/1). The crude crystals wererecrystallized from ethanol-n-hexane to obtain 39.5 g of6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.

White powder.

Melting point: 141.5°-142.5° C.

Example 5

To 1 l of 1,2-dichloroethane were added 56.8 g of titaniumtetraisopropoxide, 168 g of D-(-)-diethyl tartarate, 0.91 ml of waterand 80 g of6-{3-[1-(2-methylphenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril.The mixture was stirred and then cooled to -5° C. Thereto was added 124g of cumene hydroperoxide slowly. After the completion of the addition,the mixture was stirred at 5° C. for 18 hours. The reaction wasrepeated. The reaction mixtures from the two reactions were combined andpurified by a silica gel column chromatography (eluant:dichloromethane/ethyl acetate/methanol=3/1/0→30/10/1), followed byrecrystallization from ethanol-ethyl acetate. The mother liquor wasconcentrated to obtain crystals. This procedure was conducted 14 times.The resulting crystals were purified by a silica gel columnchromatography (eluant: dichloromethane/ethyl acetate/methanol=30/10/1),followed by recrystallization from ethanol to obtain 2.7 g of(S)-(+)-6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.White powder.

Optical purity: 97.9% (enantiomer excess)

[α]_(D) ²⁴ : +17.2° (C=1.0, methanol)

Melting point: 124.5°-126.5° C.

Example 6

7.5 g of(R)-(-)-6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyrilwas obtained by using 600 ml of dichloroethane, 38.2 ml of titaniumtetraisopropoxide, 86.5 ml of L-(+)-diethyl tartarate, 50 g of6-{3-[1-(2-methylphenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril,75 ml of cumene hydroperoxide and 0.57 ml of water and by using the sameprocedure as in Example 5. White powder (recrystallized from ethylacetate).

Optical purity: 96.6% (enantiomer excess)

[α]_(D) ²⁴ : -16.6° (c=1.0, methanol)

Melting point: 124°-126° C.

The high performance liquid chromatography used for measurement ofoptical purity was conducted under the following conditions.

Column: ULTRON ES-OVM 4.6 mm×150 mm (a product of Shinwa ChemicalIndustries, Ltd.)

Mobile phase: acetonitrile/20 mM KH₂ PO₄ aq.=8/92

Flow rate: 0.8 ml/min

Ultraviolet light: 254 nm

Retention time: 24.5 minutes

The compounds shown in Table 1 were obtained by using suitable startingmaterials and by using the same procedure as in Examples 1-4.

                                      TABLE 1                                     __________________________________________________________________________     ##STR25##                                                                    Example               Crystal form   Melting point                            No.  R.sup.1                                                                           n R          (Recrystallization solvent)                                                                  (°C.)                             __________________________________________________________________________    7    H   3                                                                                ##STR26## White powder (Ethanol-n-hexane)                                                              141.5-142.5                              8    H   3                                                                                ##STR27## Yellow powder (Ethanol-diisopropyl                                                           135 (decomposed)                         9    H   3                                                                                ##STR28## White powder (Ethanol-n-hexane)                                                              132-134                                  10   H   3                                                                                ##STR29## White powder (Ethanol)                                                                       124.5-126.5                              11   H   3                                                                                ##STR30## White powder (Ethyl acetate)                                                                 124-126                                  12   H   3                                                                                ##STR31## Colorless prisms (Ethanol-n-hexane)                                                          160-161                                  13   H   3                                                                                ##STR32## White powder (Ethanol-diisopropyl                                                            157-160                                  14   H   3                                                                                ##STR33## White powder (Ethanol-diisopropyl                                                            141-143                                  15   H   3                                                                                ##STR34## Colorless prisms (Ethanol-n-hexane)                                                          133.5-135                                16   8-CH.sub.3                                                                        3                                                                                ##STR35## White powder (Ethanol-diisopropyl                                                            137-139.5                                17   8-F 3                                                                                ##STR36## White powder (Dichloromethane- diethyl                                                       150-151                                  18   H   2                                                                                ##STR37## White powder (Ethanol-diisopropyl                                                            140-143                                  __________________________________________________________________________     (*)Compound of Example 10 is a (S)(+)-form                                    (**)Compound of Example 11 is a (R)(-)-form                              

In Table 1, the compound of Example 10 is a (S)-(+) substance and its[α]_(D) ²⁴ is 17.2° (c=l 0, methanol). The compound of Example 11 is a(R)-(-) substance and its [α]_(D) ²⁴ is -16.6° (c=1.0, methanol).

Pharmacological Test

[Test method]

Wistar strain male rats [6-week age, about 200 g (body weight)] wereanesthetized with pentobarbital. Into the thoracic aortic lumen of eachanesthetized rat was inserted a balloon catheter (Fogarty 2Fmanufactured by Baxter Health Care Corporation), and the catheter wasexpanded to injure, by abrasion, the tunica intima of the thoracicaorta. Then, each rat was allowed to stand at room temperature for 10minutes under anesthetization. Thereafter, a 10% formalin neutral buffersolution was circulated from the heart of each rat to the whole bodyunder a pressure of about 100 mm H₂ O for about 1-2 minutes. Thethoracic aorta was separated carefully, refixed and then cut in thecrosswise direction to prepare dyed thin slices. Each slice was observedby a microscope to measure the density of platelets adhered onto theinjured inside of the thoracic aorta. Each test compound was made into a5% suspension in acacia; the suspension was orally administered at adose of 30 mg (test compound)/kg (body weight); and the above test wasconducted 1-2 hours after the administration.

[Evaluation]

The density of platelets adhered onto the entire circumference of lumenof each dyed thin slice of thoracic aorta was measured visually by aplurality of examiners. The evaluation of measurement was conducted bythe following standard.

-: Platelets are adhered continuously and seen nearly on the entirecircumference.

+: Platelets are adhered continuously and seen at some intervals on thecircumference.

++: Platelets are adhered continuously in some portions of thecircumference and discontinuous in other portions.

+++: Platelets are seen on the entire circumference but only slightly.

                  TABLE 2                                                         ______________________________________                                                         Dosage   Inhibition of                                       Test compound    (mg/kg)  platelets adhesion                                  ______________________________________                                        Compound of Example 7                                                                          30       +++                                                 Compound of Example 8                                                                          30       +++                                                 Compound of Example 9                                                                          30       +++                                                 Compound of Example 10                                                                         30       ++                                                  Compound of Example 11                                                                         30       ++                                                  Compound of Example 12                                                                         30       ++                                                  Compound of Example 13                                                                         30       ++                                                  Compound of Example 14                                                                         30       ++                                                  Compound of Example 15                                                                         30       ++                                                  Compound of Example 16                                                                         30       ++                                                  Compound of Example 17                                                                         30       ++                                                  Compound of Example 18                                                                         30       ++                                                  Reference compound A***                                                                        30       -                                                                    100      +                                                   ______________________________________                                         ***Reference compound A is                                                    6{3-[1-(2-methylphenyl)-2-imidazolyl]-thiopropoxyl-3,4-dihydrocarbostyril     (the compound of Example 35 in EPA-0240015).                             

In the above test, each test compound was administered to a group offive rats, and there were prepared three slices per each rat.

We claim:
 1. A carbostyril compound of the formula (1): ##STR38## wherein R¹ is a hydrogen atom, a fluorine atom or a methyl group; R is a group of the formula: ##STR39## (wherein R² is a methyl group, a trifluoromethyl group or a nitro group), or a group of the formula: ##STR40## (wherein R³ is a fluorine atom and p is an integer of 2 or 3); and n is an integer of 2 or 3 or a salt thereof.
 2. The carbostyril compound of claim 1, wherein R¹ is a hydrogen atom.
 3. The carbostyril compound of claim 1, wherein R¹ is a fluorine atom or a methyl group.
 4. The carbostyril compound of claim 2, wherein R is a group of the formula: ##STR41## .
 5. The carbostyril compound of claim 2, wherein R is a group of the formula: ##STR42## .
 6. The carbostyril compound of claim 3, wherein R is a group of the formula: ##STR43## .
 7. The carbostyril compound of claim 3, wherein R is a group of the formula: ##STR44## .
 8. The carbostyril compound of claim 4 or 6, wherein R² is a methyl group.
 9. The carbostyril compound of claim 4 or 6, wherein R² is a trifluoromethyl group or a nitro group.
 10. A pharmaceutical composition for inhibiting the adhesion of platelets, which contains as the active ingredient a carbostyril compound or salt thereof of claim 1 and a pharmaceutically acceptable carrier.
 11. (S)-(+)-6-{3-[1-(2-Methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
 12. (R)-(-)-6-{3-[1-(2-Methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
 13. 6-{3-[1-(2-Methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril. 